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IGF2BP1-regulated expression of ERRα is involved in metabolic reprogramming of chemotherapy resistant osteosarcoma

Qing He1, Peng Hao1, Gang He2

  • 1Department of Surgical Intensive Care Unit, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Journal of Translational Medicine
|August 2, 2022
PubMed

Insights

Drug resistance in osteosarcoma (OS) is a major challenge. This study reveals that the IGF2BP1/ERRα axis drives metabolic reprogramming, contributing to doxorubicin resistance in OS cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Doxorubicin (Dox) is a primary treatment for osteosarcoma (OS).
  • Acquired drug resistance significantly limits Dox's efficacy in OS treatment.
  • Understanding the mechanisms of chemoresistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate metabolic reprogramming in Dox-resistant OS cells.
  • To identify the regulatory mechanisms underlying chemoresistance in OS.
  • To explore the role of estrogen-related receptor alpha (ERRα) and its associated pathways in Dox resistance.

Main Methods:

  • Comparative analysis of metabolic profiles (ATP, lactate, glucose, oxygen consumption) between Dox-resistant and parental OS cells.
  • Investigation of ERRα expression and its impact on metabolic reprogramming via targeted inhibition.
  • Mechanistic studies on ERRα mRNA stability, including N6-methyladenosine modification and IGF2BP1 recruitment.
  • In vitro and in vivo validation of the IGF2BP1/ERRα axis in Dox-resistant OS cells.
  • Clinical analysis correlating IGF2BP1 and ERRα expression with OS progression.

Main Results:

  • Dox-resistant OS cells exhibit significantly increased ATP levels, lactate generation, glucose consumption, and oxygen consumption rate.
  • Increased ERRα expression is implicated in metabolic reprogramming in chemoresistant OS cells; its inhibition reverses these metabolic shifts.
  • ERRα mRNA stability, not transcription, is increased in chemoresistant cells, mediated by N6-methyladenosine modification and IGF2BP1 recruitment.
  • IGF2BP1 knockdown downregulates ERRα, reverses metabolic alterations, and inhibits the oncogenic effect of the IGF2BP1/ERRα axis.
  • Elevated IGF2BP1 and ERRα expression levels correlate with clinical progression in OS patients.

Conclusions:

  • The IGF2BP1/ERRα axis plays a critical role in regulating metabolic reprogramming in Dox-resistant OS cells.
  • This axis contributes significantly to the development of chemoresistance in osteosarcoma.
  • Targeting the IGF2BP1/ERRα pathway presents a potential therapeutic strategy for overcoming Dox resistance in OS.
Keywords:
DoxorubicinEstrogen-related receptor alphaInsulin-like growth factor 2 mRNA binding protein 1N6‑methyladenineOsteosarcoma

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